Topical therapy permits drug application to a specific disease site in high concentrations with little systemic influence. This can yield more efficient dosages which minimizes the potential of side effects.
The percutaneous absorption of a drug varies greatly dependant on numerous factors. Little quantitative data is available on permeation of specific drugs, but there is a general knowledge of the issues which effect permeation of the skin. The principal barrier to permeation is the stratum corneum. It is desirable to provide a topical dosage form which will be physically and chemically stable, cosmetically acceptable to the patient, and adequately/efficiently transport the active drug to the site of action. This is difficult when the drug is a natural protein which degrades when standing over a period of time in warm weather and even at room temperature.
The search for a suitable vehicle for serine protease inhibitors must take into account the following parameters:
1. Compatibility
2. Stability
3. Physiological Inertness
4. Promotion of Bioavailabiity
5. Easy Spreadability
6. Resistance to Microbial Growth
7. Sufficient Capacity
8. Cosmetic Acceptability
The ideal vehicle would be one that is very stable and would withstand storage over a considerable period of time and temperature range without deterioration.
The ideal vehicle should be relatively inert pharmacologically and physiologically. An exception is a base that moisturizes or hydrates the dermis and thereby increases penetration. If the vehicle either moisturizes the skin directly or prevents the loss of moisture from the skin, it may enhance permeation of the drug. In this scenario, the physiological action of the vehicle would be desirable and beneficial.
Otherwise, it is important that the vehicle have little or no effect on the skin. It should be free of irritating or sensitizing properties. The ideal vehicle should be non-reactive with the drug itself. In other words the vehicle should not interfere with the bioavailability of the drug and if possible it should promote the absorption of the drug by the base.
The components of the base must be compatible with each other. Surfactants, emulsifying agents, and preservatives must all be compatible with each other as well as with the drug if they are to be used successfully.
For clinical purposes it is advisable to have a vehicle that will remain stable for at least six months, that requires no major compounding at the time of dispensing and will remain stable at a temperature range roughly between 5 and 50 degrees Centigrade.
The vehicle itself should have no physiological action apart from its role of carrying the active ingredient. Ideally, we are seeking an agent that is neither irritating or sensitizing.
If the drug, namely the serine protease inhibitor, is to be effective topically it must be available to penetrate the dermis. This means it must be released by the base or carried with the base across the skin barrier. If the skin is intact, the base may facilitate this action by softening or hydrating the superficial epidermal tissue if that tissue has become dry, cracked or impervious to penetration. Theoretical an ideal base could alter the membrane permeability of the skin. The actual permeability of skin to a number of drugs is accurately correlated with the water solubility and mineral oil/water partition coefficient of the drug. Ionization of the drug is also a very important factor so the pH of both the drug and the vehicle must be taken into consideration.
The efficacy of any topical medication is dependant on the intimate contact of the vehicle and drug with the skin. A vehicle which will not coat or spread evenly is not capable of providing the free and close contact we desire.
Frequently, ointment and cream bases have turned out to be excellent growth mediums for bacteria. This is definitely undesirable and possible contamination of the skin cannot be risked. We need to consider the various antibacterials and preservatives available in light of the characteristics of the drug itself.
It is not only essential that the vehicle meet all of the above qualification, it must be capable of holding a sufficient concentration of the drug in a homogenous state and reasonable volume.
Cosmetic acceptability involves several areas of concern. A topical product should be easily applied to the skin. It is essential that the vehicle be readily spreadable to assure compliance and to avoid irregular concentrations of the drug on the skin because of uneven application of the preparation. The ease of application and removal of the vehicle can determine whether or not the treatment program is adhered to. The frequency of application if another property that must be considered. Properties of the vehicle can determine if the drug must be applied frequently, it may be easily removed by evaporation, friction, etc. A vehicle that requires prolonged soaks or wet dressings can also negatively affect compliance. Vehicles that feel sticky, greasy or slimy, that stain clothes, skin and everything else that is touched are also not acceptable. Additional problems with compliance can occur if the vehicle is not cosmetically pleasant or acceptable to the patient. It is preferable to have a vehicle that not only feels pleasant on the skin, but one that does not bring attention to its use. In this particular context color and odor are very important characteristics.